Anu Muona

University of Eastern Finland, Kuopio, Province of Eastern Finland, Finland

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Publications (14)71.23 Total impact

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    ABSTRACT: Cerebral ischemia is a risk factor for Alzheimer's disease (AD). Moreover, recent evidence indicates that it is a two-way street as the incidence rate of stroke is significantly higher in AD patients than those without the disease. Here we investigated the interaction of ischemic brain insults and AD in 9-month-old ApdE9 mice, which show full-blown accumulation of Aβ deposits and microgliosis in the brain. Permanent occlusion of the middle cerebral artery (pMCAo) resulted in 36% larger infarct in ApdE9 mice compared to their wild-type (wt) controls. This was not due to differences in endothelium-dependent vascular reactivity. Treatment with human intravenous immunoglobulin (IVIG) reduced the infarct volumes and abolished the increased vulnerability of ApdE9 mice to pMCAo induced brain ischemia. When the mice were exposed to global brain ischemia (GI), an insult of hippocampal cells, ApdE9 mice showed increased neuronal loss in CA2 and CA3 subregions compared to their wt controls. GI was associated with increased microgliosis, astrogliosis, infiltration of blood-derived monocytic cells, and neurogenesis without clear differences between the genotypes. IVIG treatment prevented the GI-induced neuron loss in hippocampal CA1 and CA3 regions in ApdE9 mice. IVIG treatment increased microgliosis in wt but not in ApdE9 mice. Finally, GI induced 60% reduction in the hippocampal Aβ burden in ApdE9 mice, which was not affected by IVIG treatment. The results indicate that the AD pathology with Aβ deposits and microgliosis increases ischemic vulnerability in various brain areas. Moreover, IVIG treatment may be beneficial especially in patients suffering from both acute ischemic insult and AD.
    Aging and disease. 04/2014; 5(2):76-87.
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    ABSTRACT: Accumulation of amyloid β (Aβ) is a major hallmark in Alzheimer's disease (AD). Bone marrow derived monocytic cells (BMM) have been shown to reduce Aβ burden in mouse models of AD, alleviating the AD pathology. BMM have been shown to be more efficient phagocytes in AD than the endogenous brain microglia. Because BMM have a natural tendency to infiltrate into the injured area, they could be regarded as optimal candidates for cell-based therapy in AD. In this study, we describe a method to obtain monocytic cells from BM-derived haematopoietic stem cells (HSC). Mouse or human HSC were isolated and differentiated in the presence of macrophage colony stimulating factor (MCSF). The cells were characterized by assessing the expression profile of monocyte markers and cytokine response to inflammatory stimulus. The phagocytic capacity was determined with Aβ uptake assay in vitro and Aβ degradation assay of natively formed Aβ deposits ex vivo and in a transgenic APdE9 mouse model of AD in vivo. HSC were lentivirally transduced with enhanced green fluorescent protein (eGFP) to determine the effect of gene modification on the potential of HSC-derived cells for therapeutic purposes. HSC-derived monocytic cells (HSCM) displayed inflammatory responses comparable to microglia and peripheral monocytes. We also show that HSCM contributed to Aβ reduction and could be genetically modified without compromising their function. These monocytic cells could be obtained from human BM or mobilized peripheral blood HSC, indicating a potential therapeutic relevance for AD.
    Journal of Cellular and Molecular Medicine 07/2011; 16(5):1060-73. · 4.75 Impact Factor
  • Alzheimer's and Dementia 07/2011; 7(4). · 17.47 Impact Factor
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    ABSTRACT: Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BM-associated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin α4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed in Lama4-/- single knock-out mice. Moreover, the Col15a1-/-;Lama4-/- double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. The Lama4-/- knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneous Col15a1-/- knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas the Lama4-/- and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1-/-). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin α4 leads to a DKO phenotype distinct from those of both single knock-outs.
    Journal of Neuroscience 10/2010; 30(43):14490-501. · 6.91 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a dementing neurodegenerative disorder without a cure. The abnormal parenchymal accumulation of beta-amyloid (Abeta) is associated with inflammatory reactions involving microglia and astrocytes. Increased levels of Abeta and Abeta deposition in the brain are thought to cause neuronal dysfunction and underlie dementia. Microglia, the brain resident cells of monocytic origin, have a potential ability to phagocytose Abeta but they also react to Abeta by increased production of proinflammatory toxic agents. Microglia originate from hemangioblastic mesoderm during early embryonic stages and from bone marrow (BM)-derived monocytic cells that home the brain throughout the neonatal stage of development. Recent studies indicate that BM or blood-derived monocytes are recruited to the diseased AD brain, associate with the Abeta depositions, and are more efficient phagocytes of Abeta compared with resident microglia. The clearance of Abeta deposition by these cells has been recently under intensive investigation and can occur through several different mechanisms. Importantly, peripheral monocytic cells of patients with AD appear to be deficient in clearing Abeta. This review will summarize the findings on the role of blood-derived cells in AD and discuss their therapeutic potential for treating patients suffering from this devastating disease.
    Glia 02/2010; 58(8):889-900. · 5.07 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2009; 5(4).
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    ABSTRACT: Generation of double knockout mice for collagen types XV and XVIII indicated surprisingly that the mice are viable and do not suffer from any new major defects. Although the two collagens are closely related molecules sharing similarities in tissue expression, we conclude that their biological roles are essentially separate, that of type XV in muscle and type XVIII in the eye. Detailed comparisons of the null mice eyes indicated that type XV collagen seems to be involved in the tunica vasculosa lentis regression process, whereas type XVIII is in the regression of vasa hyaloidea propria, and only minor compensatory effects could be detected. Furthermore, the essential role of type XVIII collagen in the eye is highlighted by the occurrence of this collagen in the epithelial basement membranes of the iris and the ciliary body and in the inner limiting membrane of the retina, sites lacking type XV.
    Matrix Biology 10/2003; 22(5):443-8. · 3.19 Impact Factor
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    ABSTRACT: Lack of type XV collagen in mice results in mild skeletal myopathy and increases vulnerability to exercise-induced skeletal muscle and cardiac injury [Proc. Natl. Acad. Sci. USA 98 (2001), 1194]. The expression of type XV collagen was studied during murine fetal development from 10.5 to 18.5 dpc using immunofluorescence. The first sign of type expression was seen in the capillaries of many tissues at 10.5 dpc, some of them showing developmental transitions in the expression. Interestingly, capillaries forming the blood-brain barrier and those of the sinusoidal type were essentially lacking in this collagen. Early expression was also detected in the skeletal muscle and peripheral nerves, while expression in the heart, kidney and lung appeared to be developmentally regulated. In addition, distinct staining was found in the perichondrium of the cartilage. Collectively, the dynamics of its expression during development, its localization in the basement membrane--fibrillar matrix interface and the consequences of its absence in mice suggest a structural role in providing stability at least in skeletal muscle and capillaries. The early prominent expression of type XV collagen in newly forming blood vessels could also indicate a possible role in angiogenic processes.
    Matrix Biology 02/2002; 21(1):89-102. · 3.19 Impact Factor
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    ABSTRACT: Type XV collagen occurs widely in the basement membrane zones of tissues, but its function is unknown. To understand the biological role of this protein, a null mutation in the Col15a1 gene was introduced into the germ line of mice. Despite the complete lack of type XV collagen, the mutant mice developed and reproduced normally, and they were indistinguishable from their wild-type littermates. However, Col15a1-deficient mice showed progressive histological changes characteristic for muscular diseases after 3 months of age, and they were more vulnerable than controls to exercise-induced muscle injury. Despite the antiangiogenic role of type XV collagen-derived endostatin, the development of the vasculature appeared normal in the null mice. Nevertheless, ultrastructural analyses revealed collapsed capillaries and endothelial cell degeneration in the heart and skeletal muscle. Furthermore, perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus, type XV collagen appears to function as a structural component needed to stabilize skeletal muscle cells and microvessels.
    Proceedings of the National Academy of Sciences 02/2001; 98(3):1194-9. · 9.81 Impact Factor
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    ABSTRACT: Type XV collagen occurs widely in the basement membrane zones of tissues, but its function is unknown. To understand the biological role of this protein, a null mutation in the Col15a1 gene was introduced into the germ line of mice. Despite the complete lack of type XV collagen, the mutant mice developed and reproduced normally, and they were indistinguishable from their wild-type littermates. However, Col15a1-deficient mice showed progressive histological changes characteristic for muscular diseases after 3 months of age, and they were more vulnerable than controls to exercise-induced muscle injury. Despite the antiangiogenic role of type XV collagen-derived endostatin, the development of the vasculature appeared normal in the null mice. Nevertheless, ultrastructural analyses revealed collapsed capillaries and endothelial cell degeneration in the heart and skeletal muscle. Furthermore, perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus, type XV collagen appears to function as a structural component needed to stabilize skeletal muscle cells and microvessels.
    Proceedings of the National Academy of Sciences 01/2001; 98(3):1194-1199. · 9.81 Impact Factor
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    ABSTRACT: Isolation and characterization of the mouse gene for the alpha1 chain of type XV collagen (Col15a1) revealed it to be approximately 110 kb in length and contain 40 exons. Analysis of the proximal 5'-flanking region showed properties characteristic of a housekeeping gene promoter, such as an absence of TATA and CAAT boxes, the presence of several transcriptional start sites and a high G+C content. The general organization of the mouse Col15a1 gene was found to be highly similar to that of its human homologue, but the genomic area encoding the end of the N-terminal non-collagenous domain showed marked divergence from the human form. Furthermore, two exons coding for the N-terminal collagenous domain of the human alpha1(XV) chain are lacking in the mouse Col15a1 gene. Due to the lack of two exons and a codon divergence in one exon, the mouse alpha1(XV) chain contains seven collagenous domains, whereas the human equivalent contains nine. Comparison of 5'-flanking sequences indicated four domains that were conserved between the mouse and human genes. Functional analysis of the mouse promoter identified cis-acting elements for both positive and negative regulation of Col15a1 gene expression in mouse NIH/3T3 cells.
    Matrix Biology 12/2000; 19(6):489-500. · 3.19 Impact Factor
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    ABSTRACT: The human gene for the alpha1 chain of type XV collagen (COL15A1) is about 145 kilobases in size and contains 42 exons. The promoter is characterized by the lack of a TATAA motif and the presence of several Sp1 binding sites, some of which appeared to be functional in transfected HeLa cells. Comparison with Col18a1, which encodes the alpha1(XVIII) collagen chain homologous with alpha1(XV), indicates marked structural homology spread throughout the two genes. The mouse Col18a1 contains one exon more than COL15A1, due to the fact that COL15A1 lacks sequences corresponding to exon 3 of Col18a1, which encodes a cysteine-rich sequence motif. Twenty-five of the exons of the two genes are almost identical in size, six of them contain conserved split codons, and the locations of the respective exon-intron junctions are identical or almost identical in the two genes. The homologous exons include the closely adjacent first pair of exons and the exons encoding a thrombospondin-1 homology found in the N-terminal noncollagenous domain 1, which are followed by the most variable part of the two genes, covering the C-terminal half of their noncollagenous domain 1 and the beginning of the collagenous portion, after which most of the exons are homologous. The lengths of the introns are not similar in these genes, with two exceptions, namely the first intron, which is very short, less than 100 base pairs, and the second intron, which is very large, about 50 kilobases, in both genes. It can be concluded that COL15A1 and Col18a1 are derived from a common ancestor.
    Journal of Biological Chemistry 08/1998; 273(28):17824-31. · 4.65 Impact Factor
  • Matrix Biology 01/1996; 15(3):160-160. · 3.19 Impact Factor
  • Matrix Biology. 09/1994; 14(5):351–352.

Publication Stats

213 Citations
71.23 Total Impact Points

Institutions

  • 2010–2011
    • University of Eastern Finland
      • A.I. Virtanen Institute for Molecular Sciences
      Kuopio, Province of Eastern Finland, Finland
  • 1998–2010
    • University of Oulu
      • • Department of Medical Biochemistry and Molecular Biology
      • • Department of Pharmacology and Toxicology
      Uleoborg, Oulu, Finland